Will your competent? doctor create protocols out of this, especially the BDNF part which your doctor has known of for well over a decade?
- BDNF
(202 posts to April 2011)
Do you prefer your doctor, hospital and board of director's incompetence NOT KNOWING? OR NOT DOING? Your choice; let them be incompetent or demand action!
The Secret of Superagers’ Cognitive Longevity Revealed?
The brains of superagers — octogenarians with a memory capacity that rivals that of younger adults — generate more than twice as many new neurons as typical older adults and 2.5 times as many as those with Alzheimer’s disease (AD), a new study shows.
The findings, drawn from an analysis of postmortem hippocampal tissue, could explain superagers’ cognitive preservation and answer one of the most contentious questions in neuroscience: Can the adult brain produce new neurons?
Investigators said the neurogenesis they identified in superagers may be a ‘resilience signature’ of exceptional cognitive aging.
The study was published online on February 25 in Nature.
A Long-Contested Question
Whether the adult human brain generates new neurons has been a longtime topic of debate. Animal research has established that the hippocampus produces fresh neurons throughout life in rodents and that this process supports learning and memory, but efforts to confirm the same phenomenon in humans have yielded conflicting results.
Recent studies have begun to tip the balance, confirming the presence of immature neurons in the adult human hippocampus and showing that their numbers decline in people with AD.
The epigenetic mechanisms governing that process and their relationship to cognitive function have remained poorly understood. To address that gap, researchers analyzed postmortem hippocampal tissue from 38 individuals using paired single-nucleus RNA sequencing and chromatin accessibility profiling on nearly 356,000 neuronal cells.
Patients were divided into five groups, including cognitively healthy young and older adults, superagers, individuals with mild or early dementia, and patients with diagnosed AD.
The analysis revealed that superagers had roughly 2.5 times more immature neurons than individuals with AD and approximately twice as many as healthy older adults. While the comparison between superagers and healthy older adults did not reach statistical significance, superagers possessed significantly more neuroblasts than the AD group (q = 0.0002).
In contrast, people with AD had markedly fewer neuroblasts and immature neurons than either young or healthy older adults (P < .05). Instead, they showed a significant accumulation of neural stem cells (P < .05) that were unable to differentiate and become mature neurons. That accumulation has a negative effect on cognitive function, researchers said.
In superagers, by contrast, the neurogenic pipeline appears intact, with stem cells successfully differentiating into the neuroblasts and immature neurons that support memory formation.
“Neurogenesis is a very profound form of plasticity,” Orly Lazarov, PhD, professor of neuroscience in the Department of Anatomy and Cell Biology at the University of Illinois, Chicago, told Medscape Medical News. “I would expect if it’s connected or somehow associated with cognition in the human brain, it would show greater extent and a distinct profile in the superagers. And it showed both.”
Beyond Neurogenesis
The findings also revealed that most molecular differences across cognitive groups were driven not by changes in gene expression, but by changes in accessibility of chromatin — the structural packaging of DNA that regulates gene expression.
Investigators also identified molecular signals in other hippocampal cell types — particularly CA1 neurons and astrocytes — that distinguished superagers and healthy older adults from those with preclinical pathology and AD.
Superagers shared many of the same gene regulatory network signatures as young adults, including similar transcription factor programs, but also exhibited unique regulatory features not seen in any other group.
Among the key genes upregulated in superager neuroblasts and immature neurons was BDNF, which encodes brain-derived neurotrophic factor, a protein critical for neuronal survival and synaptic plasticity.
“The epigenetics is a long-term picture,” Jalees Rehman, MD, Benjamin J. Goldberg Professor and head of the Department of Biochemistry and Molecular Genetics at the University of Illinois at Chicago, told Medscape Medical News. “And I think that is why, if there were differences between cognitive groups, we would expect them to be more visible consistently in the epigenetic state.”
Reframing Patient Discussions
The findings could reframe how clinicians discuss cognitive aging with patients, Rehman said.
“Knowing that there is a neurogenic process that’s active even in your 80s…that our brain has an amazing regenerative capacity that persists in old age, is a very important piece of information to share with patients,” he said.
The epigenetic landscape of the brain may not be fixed, Rehman noted, adding that it might reflect the cumulative effects of cognitive stimulation, exercise, and other beneficial lifestyle interventions, which is important to share with patients who want to preserve their cognitive function as they age.
Combining targeted therapeutics with lifestyle interventions may ultimately prove more effective than either approach alone, the investigators suggested, adding that larger, prospectively characterized cohort studies are needed.
The researchers acknowledged several important constraints. The study relied on postmortem tissue from a relatively small cohort, with high inter-sample variability in cell-type abundance that limited statistical power.
Causality also has not been established, which investigators said is why they referred to the neurogenesis pattern they identified in superagers as a resilience “signature.”
The next step in their research is to identify upstream cues that activate the transcription factor programs their study mapped. “Can we repurpose existing drugs to activate those signaling pathways?” Rehman said.
Changing the Narrative
The findings provide a much-needed challenge to the “inevitable” narrative of cognitive decline, Amanda Cook Maher, PhD, clinical assistant professor at the University of Michigan, Ann Arbor, Michigan, told Medscape Medical News.
Maher, who was not part of the study, is a core investigator with the Multisite SuperAging Research Initiative.
“Maybe this is sort of a missing link that we haven’t really looked into very much, and what could potentially push the field forward,” she said.
While the small sample size is a limitation, the study’s scope — spanning the entire spectrum from young adults to those with AD and superagers — is a strength.
Regarding the lifestyle factors mentioned by the authors, Maher noted that while factors such as exercise and diet differentiate healthy aging from AD, the unique ‘resilience signature’ found here might help explain superagers’ cognitive longevity.
Overall, the study of superagers brings a necessary sense of “hope and excitement” to a field that often focuses exclusively on what goes wrong in the brain, Maher said.
“The story we’ve sort of been told — that cognitive decline is inevitable, and your brain cannot grow new neurons — maybe isn’t the case,” she said.
The study was supported by the National Institute on Aging. Lazarov, Rehman, and Maher reported no relevant financial relationships.
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